Comparing the effectiveness of hyperimmune plasma and plasmapheresis in COVID-19 patients

the effectiveness of hyperimmune plasma and plasmapheresis in COVID-19


Introduction
Since the end of December 2019, a new coronavirus was identified after people got pneumonia for no reason (1,2).Coronaviruses are a large family of RNA viruses that range from the common cold virus to the cause of more severe diseases such as severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS).This new virus was later known as acute respiratory syndrome coronavirus 2, and due to its high contagiousness, it spreads very quickly in China and worldwide (3)(4)(5)(6)(7)(8).This highly contagious infectious disease is conveyed by close contact (9,10).
The immune response is critical to controlling and eliminating the covid disease.However, the uncontrolled response of the immune system to the virus can play an essential role in the pathogenesis of the disease.Patients with severe forms have been reported to have high levels of pro-inflammatory cytokines.The cytokine storm may play an essential role in the pathogenesis of viral acute respiratory syndrome (11,12).Apheresis therapy is a method in which different components of blood are separated.In plasmapheresis or therapeutic Introduction: In December 2019, the first clinical signs of patients infected with SARS CoV 2 surfaced, then the fatality rate rose daily with no available definitive therapy.Objectives: Considering the necessity for more research into plasma therapy, the urgency of treating patients with a severe disease, and the lack of comparable studies, we compared the effectiveness of hyperimmune plasma and plasmapheresis in COVID-19 patients.

Patients and Methods:
In this quasi-experimental study, 38 patients with severe COVID-19 were enrolled in two groups of 19 individuals treated with plasmapheresis and hyperimmune plasma after matching for severity.The researcher documented the patient's information on a checklist submitted for statistical analysis using the SPSS software.Results: Patients comprised 60.53% of men and 39.5% of women.In this study, 60.53% of patients had underlying conditions, including hypertension and diabetes.The mean length of hospitalization for patients in the hyperimmune plasma group was considerably shorter than those in the plasmapheresis group (P < 0.05).

Conclusion:
The average hospitalization time for patients who received hyperimmune plasma was considerably shorter than the plasmapheresis group.As a result, patients are encouraged to utilize this type of plasma at the earliest stages of the condition.plasma exchange, a large amount of plasma is taken from the patient in each session.Depending on the clinical conditions, fresh frozen plasma(FFP), albumin, and crystalloid materials such as isotonic saline are replaced.Some side effects of FFP include; allergy, transfusionrelated acute lung injury(TRALI), and the possibility of transmitting viral agents.Additionally Injecting FFPcontaining IgA into a person with selective IgA deficiency causes severe side effects.
Currently, it is estimated that 13.8% of the infected cases have the acute form of the disease, while 6.1% have the more severe form (13).The administration of plasma from recovered people under the name of hyperimmune plasma is one of the new treatments used.Considering the history of using this modality to treat other diseases, such as influenza, this treatment has become more important (14).Since starting the treatment at the beginning of the acute form of the patient is more effective, this method should not be delayed, and the emergency implantation of a temporary double-lumen catheter is a priority.Plasmapheresis is performed by two methods of centrifugal apheresis and membrane plasma separation, since the centrifugal apheresis method is preferred.The centrifugal apheresis can be conducted in 3 to 5 sessions (usually, five sessions are performed, since rarely more sessions are needed).In the case of FFP, it should be noted that ABO compatibility is necessary.

Objectives
Considering the need for more research into plasma therapy, the urgency of treating patients with a severe form of the disease, and the lack of comparable studies, we compared the effectiveness of hyperimmune plasma and plasmapheresis in COVID-19 patients.

Study design
This quasi-experimental study was conducted in 2021 on 38 patients with severe COVID-19 in two groups of 19 individuals at Shahid Mohammadi hospital.The study included patients who met specific criteria for inclusion and exclusion.Patients with immunodeficiency diseases, end-stage renal disease, moderate and severe renal failure, a history of malignancy, myocardial infarction, unstable angina, pregnant women, and stage II hypertension were excluded from the study.Patients with positive COVID-19 polymerase chain reaction (PCR) and SPO 2 <93% were included if they did not meet the exclusion criteria and had at least three characteristics of severe COVID-19.The characteristics of severe COVID-19 are as follows(15): 1) Age above 60 years 2) Having an underlying disease 3) Fever above 39 °C 4) The number of lymphocytes less than 1.1×10 9 /L.5) The number of eosinophils is less than 0.02×10 9 /L 6) Platelet counts less than 125×10 9 /L 7) C-reactive protein(CPR) greater than ten mg/L 8) Lactate dehydrogenase (LDH) more than 250 units per litre 9) Hemoglobin decrease of more than 7% in 24 hours Considering the limited number of non-drug treatment cases with plasmapheresis and hyperimmune plasma, the census method was conducted for sampling in this study.After matching the patients in terms of severity, they were divided into two groups receiving plasmapheresis and hyperimmune plasma.
Patients with COVID-19 who indicated plasmapheresis were treated with plasmapheresis to reduce cytokines.In each session, 2-2.5 litres of plasma were taken.According to the available facilities of the hospital, 4 to 5 units of FFP and 2 to 3 units of 20% albumin, and the rest were replaced with normal saline.Electrolyte disorders, especially calcium, was corrected before plasmapheresis.Another group of patients with indications as well received hyperimmune plasma.All patients were treated according to the protocol, including antiviral, interferon, and steroids.Then, the patients who meet the inclusion criteria in terms of the length of hospitalization and the rate of hospitalization in the intensive care unit (ICU), O 2 saturation, LDH, troponin, white blood cell (WBC), lymphocyte count, general condition, length of hospitalization, need for intubation, gender, mortality rate, and associated diseases were investigated.The research tool in this study was the checklist prepared by the researcher, which included age, gender, duration of hospitalization and ICU, underlying disease, general condition and mortality rate, LDH, CRP, O 2 saturation, troponin, and lymphocyte count.All the plasmas used in this research were prepared and used according to the national guidelines of the blood transfusion organization.

Statistical analysis
After collecting the data, it was entered into SPSS software version 21 and was evaluated by descriptive statistics (mean and standard deviation of quantitative variables and frequency percentage).Then, considering the balanced or unbalanced statistical distribution of quantitative data, Mann-Whitney U, independent T, and Wilcoxon tests were conducted for analysis, since the significance level was 0.05.Besides chi-square test was employed to analyze the qualitative data.

Results
This study was carried out on 38 COVID-19-positive patients, 19 in the hyperimmune plasma group and 19 in the plasmapheresis group.The researcher kept track of the patient's data and their tests before and throughout hospitalization.About 39.47% of patients were female, and 60.53% were male.Approximately, 60.53% of patients had underlying disease.There was no significant difference between gender and underlying disease in the two treatment groups.No significant difference was found between the age of the patients in the two treatment groups.The difference in gender and underlying disease of the two groups of patients under study was investigated.The age difference between the patients in the two study groups was evaluated (Table 1).We also examined the distribution of quantitative data in groups (Table 2).The average age in the plasmapheresis group was 49.21 ± 12.36 years; in the hyperimmune group, it was 49.95±14.93years (Table 3).
Based on the obtained information, the average duration of hospitalization of patients in the group receiving hyperimmune plasma was significantly less than those in the group receiving plasmapheresis (P<0.05).The duration of hospitalization in the ICU of patients in the group receiving hyperimmune plasma was less, but this difference was not significant (Table 4).
According to the obtained information, the difference between initial LDH and during discharge or death in the two treatment groups was not significant (P > 0.05).Additionally, the trend of LDH changes in both treatment groups was not significant (P > 0.05; Table 5).We evaluated the trend of LDH changes from the beginning of hospitalization to the day of discharge or death.
The difference between initial O 2 saturation and during discharge or death in the two treatment groups was not significant (P > 0.05).However, the increasing trend of O 2 saturation changes in the group receiving plasmapheresis was significant (P < 0.05; Table 6).We evaluated the trend of blood oxygen saturation changes from the beginning of hospitalization to the day of discharge or death.Based on the analysis, no significant difference was observed between the initial tests in the two treatment groups (Table 7).
In this study, the mortality rate of patients was not significantly related to their treatment group (P > 0.05; Table 8).

Discussion
Coronavirus (SARS-CoV-2) has attracted global attention due to its potential impact on health.There is no definitive cure for COVID-19 infection, and current management strategies focus on supportive care, infection control, and investigational therapies.
The administration of plasma from recovered people under the name of hyperimmune plasma is one of the new treatments modalities.Therefore, in this study, we compared the effectiveness of hyperimmune plasma and plasmapheresis in our patients.Mortality due to COVID-19 infection is associated with certain risk factors, which include; age, previous lung disease, diabetes, heart disease, hypertension, and stroke (16).Since, most of the patients had high blood pressure, diabetes, and kidney disorders, however in our study, no significant difference was detected between gender and the presence of underlying disease in all groups.
The length of hospitalization of patients with COVID-19 is an important parameter in the management of these patients.In this study, we observed that, the average length of hospitalization of patients in the group which received hyperimmune plasma was significantly less than that of the group who received plasmapheresis (P < 0.05).The duration of hospitalization in ICU patients in group receiving hyperimmune plasma was less, but this difference was not significant.Although in the study of Khamis et al, the conclusion was reached that due to the complications caused by plasmapheresis, the duration of hospitalization of patients increased (17).
Regarding the recovery of patients with COVID-19, some studies like the study by Winters et al could not show the absolute effectiveness of plasmapheresis.Therefore the physician may decide depending on the patient's condition (18).
Accordingly, in our study the difference between the initial LDH and during the discharge of patients or death in the two treatment groups was not significant (P>0.05).
The trend of LDH changes in both treatment groups was not significant (P > 0.05).Although the study by Altmayer et al showed, in the people who underwent plasmapheresis, the plasma LDH significantly decreased at the time of discharge, however our findings were contrary to the study by Altmayer et al (19).
One of the criteria determining the severity of the disease and the recovery process of patients with COVID-19 is the O2 saturation level of these patients.The difference between initial O2 saturation and during discharge or death in the two treatment groups was not significant (P > 0.05).However, the increasing trend of O2 saturation changes in the group receiving plasmapheresis was significant (P < 0.05).
In this study we found that hyperimmune plasma does not affect SPO 2 (blood oxygen saturation)levels.In the study of Altmayer et al, since all patients were subjected to plasmapheresis, their SPO 2 level also increased significantly at the end of the study, which confirming our results (19).
In addition, one of the laboratory criteria widely conducted for assessment the condition of COVID-19 patients is the number of blood lymphocytes.In the study by Tan and the colleagues, the lower the patient's lymphocyte count at admission was associated with the greater severity and worse prognosis (20).
Finally, in this study, we detected that the mortality rate of patients had no significant relationship with their treatment group (P > 0.05).However, in the study by Khamis et al, patients who undergo plasmapheresis have lower mortality than other patients (17).

Conclusion
In this study, the results were obtained that the average duration of hospitalization of patients in the hyperimmune plasma receiving group was significantly less than that of patients receiving plasmapheresis.Accordingly, the duration of hospitalization in the ICU patients of the hyperimmune plasma receiving group was similarly shorter, but this difference was not significant.Additionally, the mortality rate of our patients in all groups was not significantly different, however the mortality rate was higher in the hyperimmune plasma receiving group.We also found that the difference in LDH and lymphocyte count in the initial blood and during discharge or death in the two treatment groups was not significant.Likewise, the difference between troponin and CRP of patients in the two groups was not significant.

Limitations of the study
Our study was single center and was conducted on a limited number of patients.Therefore larger studies with multi-centric design suggest

Recommendations
This study should be conducted with a larger sample size and over a more extended period of time to make its results more reliable.

Table 1 .
Demographic information of patients

Table 2 .
Information about the normality of the distribution of quantitative data

Table 3 .
Comparison of the age of the studied patients in two intervention and control groups

Table 4 .
Examining the relationship between the duration of hospitalization and the amount of treatment received by the studied patients

Table 7 .
Examining the relationship between primary tests and the amount of treatment received by the studied patients

Table 5 .
Examining the relationship between LDH and the type of treatment received by the studied patients

Table 6 .
Examining the relationship between blood oxygen saturation percentage and the type of treatment received by the studied patients

Table 8 .
Examining the relationship between the number of deaths and the amount of treatment received by the studied patients